Type 1 diabetes (T1D) remains a significant global health challenge and patients with T1D need lifelong insulin therapy. Islet transplantation holds transformative potential by replacing autoimmune-mediated destruction of insulin-producing beta cells. This review examines the trajectory of islet transplantation for T1D, focusing on the process and benefits of obtaining biologics license application (BLA) approval for cell-based therapies. Following US Food and Drug Administration (FDA) approval, the authors identify key steps urgently needed to foster islet transplantation as a viable treatment for a broader population of patients with T1D. Furthermore, the authors highlight recent advances in encapsulation technologies, stem cell-derived islets, xenogeneic islets, and gene editing as strategies to overcome challenges such as immune rejection and limited islet sources. These innovations are pivotal in enhancing the safety and efficacy of islet transplantation. Ultimately, this review emphasizes that while BLA approval represents a critical milestone, realizing the full potential of cell therapy for T1D requires addressing the scientific, clinical, and logistical challenges of its real-world implementation. By fostering innovation, collaboration, and strategic partnerships, the field can transform T1D care, offering patients a durable, life-changing alternative to traditional insulin therapy.

Human engineered tissues hold great promise for therapeutic tissue regeneration and repair. Yet, development of these technologies often stalls at the stage of in vivo studies due to the complexity of engineered tissue formulations, which are often composed of diverse cell populations and material elements, along with the tedious nature of in vivo experiments. We introduce a "plug and play" platform called parallelized host apposition for screening tissues in vivo (PHAST). PHAST enables parallelized in vivo testing of 43 three-dimensional microtissues in a single 3D-printed device. Using PHAST, we screen microtissue formations with varying cellular and material components and identify formulations that support vascular graft-host inosculation and engineered liver tissue function in vivo. Our studies reveal that the cellular population(s) that should be included in engineered tissues for optimal in vivo performance is material dependent. PHAST could thus accelerate development of human tissue therapies for clinical regeneration and repair.

Islet transplantation represents a promising curative approach for type 1 diabetes by restoring glucose-responsive insulin secretion. However, the requirement for lifelong immunosuppression to prevent immune rejection can lead to significant side effects. Emerging strategies such as microencapsulation, nanoencapsulation, and hypoimmune engineering are being developed to protect transplanted islets from immune attack, thereby enhancing their viability and function. This review critically examines these innovative technologies, highlighting the methodologies, materials, experimental and clinical outcomes, as well as the challenges they face and potential solutions to overcome those challenges.

Type 1 diabetes (T1D) is a chronic autoimmune disease primarily diagnosed in childhood, characterized by pancreatic β-cell destruction, severe insulin deficiency, and hyperglycemia. Current treatments, including insulin therapy and glucose-lowering medications, manage the condition but fall short of offering a cure. In this review we explore the potential of stem-cell therapy as a transformative and curative approach for T1D, focusing on its promise in regenerating β-cells and addressing challenges specific to the pediatric population.

A comprehensive review of the literature was conducted to evaluate stem-cell types: embryonic, perinatal, adult, induced pluripotent and cancer stem cells, and their role in T1D treatment. Particular emphasis was placed on methods for β-cell differentiation, advancements in autologous and allogeneic stem-cell transplantation and emerging strategies to overcome safety, efficacy, and economic barriers. Challenges such as immune rejection, tumorigenicity, and cost-effectiveness were analyzed, alongside novel solutions like immune-shielding and clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein-9 (Cas9) technology.

Stem-cell therapy presents a promising avenue for curing T1D, offering potential for β-cell regeneration and reduced dependence on exogenous insulin. However, challenges such as delayed β-cell functionality, immune responses, tumor risks, and high costs hinder widespread application.

Advancements in personalized medicine, immune-shielding strategies, and cost reduction may pave the way for clinical success, especially in pediatric populations. Further research addressing these barriers is essential to establish stem-cell therapy as a viable and equitable treatment option.

Intrahepatic islet transplantation is a promising strategy for β-cell replacement therapy in the treatment of Type 1 Diabetes. However, several obstacles hinder the long-term efficacy of this therapy. A major challenge is the scarcity of donor organs. During the isolation process, islets are disconnected from their extracellular matrix (ECM) and vasculature, leading to significant loss due to anoikis and hypoxia. Additionally, inflammatory and rejection reactions further compromise islet survival and engraftment success. Extensive efforts are being made to improve the efficacy of islet transplantation. These strategies include promoting revascularization and ECM support through bioengineering techniques, exploring alternative sources of insulin-secreting cells, and providing immunomodulation for the graft. Despite these advancements, a significant gap remains in integrating these strategies into a cohesive approach that effectively replicates the native endocrine environment. Specifically, the lack of comprehensive methods to address both the structural and functional aspects of the endocrine niche limits reproducibility and clinical translation. Therefore, bioengineering an endocrine pancreas must aim to recreate the endocrine niche to achieve lifelong efficacy and insulin independence. This review discusses various strategies developed to produce the building blocks for generating a vascularized, immune-protected insulin-secreting construct, emphasizing the importance of the endocrine niche's composition and function.

The search for an effective cell replacement therapy for diabetes has driven the development of "perfect" pancreatic islets from human pluripotent stem cells (hPSCs). These hPSC-derived pancreatic islet-like β cells can overcome the limitations for disease modelling, drug development and transplantation therapies in diabetes. Nevertheless, challenges remain in generating fully functional and mature β cells from hPSCs. This review underscores the significant efforts made by researchers to optimize various differentiation protocols aimed at enhancing the efficiency and quality of hPSC-derived pancreatic islets and proposes methods for their improvement. By emulating the natural developmental processes of pancreatic embryogenesis, specific growth factors, signaling molecules and culture conditions are employed to guide hPSCs towards the formation of mature β cells capable of secreting insulin in response to glucose. However, the efficiency of these protocols varies greatly among different human embryonic stem cell (hESC) and induced pluripotent stem cell (hiPSC) lines. This variability poses a particular challenge for generating patient-specific β cells. Despite recent advancements, the ultimate goal remains to develop a highly efficient directed differentiation protocol that is applicable across all genetic backgrounds of hPSCs. Although progress has been made, further research is required to optimize the protocols and characterization methods that could ensure the safety and efficacy of hPSC-derived pancreatic islets before they can be utilized in clinical settings.

Yielding of dynamically crosslinked hydrogels, or the transition between a solid-like and liquid-like state, allows facile injection and utility in translational biomedical applications including delivery of therapeutic cells. Unfortunately, the time-varying nature of the transition is not well understood, nor are there design rules for understanding the effects of yielding on encapsulated cells. Here, we unveil underlying molecular mechanisms governing the yielding transition of dynamically crosslinked gels currently being researched for use in cell therapy. We demonstrate through nonlinear rheological characterization that the network dynamics of the dynamic hydrogels dictate the speed and character of their yielding transition. Rheological testing of these materials reveals unexpected elastic strain stiffening during yielding, as well as characterization of the rapidity of the yielding transition. A slower yielding speed explains enhanced protection of directly injected cells from shear forces, highlighting the importance of mechanical characterization of all phases of yield-stress biomaterials.

This opinion paper explores the path forward for islet transplantation as a cell therapy for type 1 diabetes, following the Biologics License Application (BLA) approval. The authors review key challenges and opportunities that lie ahead. After a brief overview of the history of human islet transplantation, the paper examines the FDA's regulatory stance on isolated islet cells and the requirements for obtaining a BLA. The authors discuss the significance of this approval and the critical steps necessary to broaden patient access, such as scaling up production, clinical integration, reimbursement frameworks, post-marketing surveillance, and patient education initiatives. The paper highlights that the approval of LANTIDRA as an allogeneic cell transplant for uncontrolled type 1 diabetes marks the beginning of new chapters in improving islet transplantation. The authors emphasize essential areas for development, including advancements in islet manufacturing, optimization of transplant sites, islet encapsulation, exploration of unlimited cell sources, and gene editing technologies. In conclusion, the future of islet transplantation beyond the BLA approval presents challenges and opportunities. While significant regulatory milestones have been reached, hurdles remain. Innovations in stem cell-derived islets, cell encapsulation, and gene editing show promise in enhancing graft survival, expanding the availability of transplantable cells, and reducing the reliance on immunosuppressive drugs. These advancements could pave the way for more accessible, durable, and personalized diabetes treatments.

Type 1 diabetes (T1D) is a chronic autoimmune disorder characterized by the destruction of insulin-producing beta cells in the pancreas, leading to insulin deficiency and chronic hyperglycemia. The main current therapeutic strategies for clinically overt T1D - primarily exogenous insulin administration combined with blood glucose monitoring - fail to fully mimic physiological insulin regulation, often resulting in suboptimal or insufficient glycemic control. Islet cell transplantation has emerged as a promising avenue for functionally replacing endogenous insulin production and achieving long-term glycemic stability. Here, we provide an overview of current islet replacement strategies, ranging from islet transplantation to stem cell-derived islet cell transplantation, and highlight emerging approaches such as immunoengineering. We examine the advancements in immunosuppressive protocols to enhance graft survival, innovative encapsulation, and immunomodulation techniques to protect transplanted islets, and the ongoing challenges in achieving durable and functional islet integration. Additionally, we discuss the latest clinical outcomes, the potential of gene editing technologies, and the emerging strategies for islet cell regeneration. This review aims to highlight the potential of these approaches to transform the management of T1D and improve the quality of life of individuals affected by this condition.

Immune checkpoints are important molecules that regulate the immune response, preventing its overactivation from causing tissue damage and autoimmune diseases. B and T lymphocyte attenuator (BTLA) plays an important role in regulating the activation and suppression of the immune response as part of a bidirectional signaling complex. The BTLA and its ligand herpesvirus entry mediator (HVEM) interaction transmits inhibitory signals that suppress the biological activity of T cells, B cells, and DCs. In addition, BTLA-HVEM can affect the induction of Treg cells, further suggesting its important role in immune regulation. Organ transplantation is the ultimate treatment option for many patients with end-stage organ failure. Transplant rejection can cause damage to the transplanted organ, which seriously affects the prognosis of patients. Therefore, we would like to explore the potential application value of the BTLA-HVEM interaction to exert an immunosuppressive function and thus attenuate transplant rejection. We first reviewed the structure and function of BTLA and HVEM, then summarized their research progress in organ transplantation, and further explored the directions of potential future applications and the challenges of current BTLA-HVEM applications.

This work establishes the design of a fully synthetic, shear-thinning hydrogel platform that is injectable and can isolate engineered, allogeneic cell therapies from the host. We utilized RAFT to generate a library of linear random copolymers of N,N-dimethylacrylamide (DMA) and 2-vinyl-4,4-dimethyl azlactone (VDMA) with variable mol% VDMA and degree of polymerization. Poly(DMA-co-VDMA) copolymers were subsequently modified with either adamantane (Ad) or β-cyclodextrin (Cd) through amine-reactive VDMA to prepare hydrogel precursor macromers containing complementary guest-host pairing pendant groups that, when mixed, form shear-thinning hydrogels. Rheometric evaluation of the hydrogel library enabled identification of lead macromer structures comprising 15 mol% pendants (Ad or Cd) and a degree of polymerization of 1000; mixing of these Ad and Cd functionalized precursors yielded hydrogels possessing storage modulus above 1000 Pa, tan(δ) values below 1 and high yield strain, which are target characteristics of robust but injectable shear-thinning gels. This modular system proved amenable to nanoparticle integration with surface-modified nanoparticles displaying Ad. The addition of the Ad-functionalized nanoparticles simultaneously improved mechanical properties of the hydrogels and enabled extended hydrogel retention of a model small molecule in vivo. In studies benchmarking against alginate, a material traditionally used for cell encapsulation, the lead hydrogel showed significantly less fibrous encapsulation in a subcutaneous implant site. Finally, this platform was utilized to encapsulate and extend in vivo longevity of inducible transgene-engineered mesenchymal stem cells in an allogeneic transplant model. The hydrogels remained intact and blocked infiltration by host cells, consequently extending the longevity of grafted cell function relative to a benchmark, shear-thinning hyaluronic acid-based gel. In sum, the new synthetic, shear-thinning hydrogel system presented here shows potential for further development as an injectable platform for delivery and in situ drug modulation of allograft and engineered cell therapies.

Late-onset hypogonadism (LOH) syndrome is characterized by age-related testosterone deficiency and negatively affects the quality of life of older men. A promising therapeutic approach for LOH syndrome is transplantation of testosterone-producing Leydig-like cells (LLCs) derived from human induced pluripotent stem cells (hiPSCs). However, previous studies have encountered obstacles, such as limited cell longevity, insufficient testosterone production, and inefficiency of differentiation. To address these issues, we developed a novel protocol that includes forced NR5A1 expression, a cytokine cocktail promoting mesoderm differentiation, and a transitional shift from 3D to 2D cultures. The resultant cells survived on culture dishes for over 16 weeks, produced 22-fold more testosterone than the conventional method, and constituted a homogeneous population of LLCs with a differentiation efficiency exceeding 99% without purification. Furthermore, these LLCs were successfully engrafted subcutaneously into mice, resulting in increased serum testosterone levels. Our study will facilitate innovative therapeutic strategies for LOH syndrome.

Background/Objectives: Human pancreatic islet transplantation shows promise for long-term glycemic control in diabetes patients. A shortage of healthy donors and the need for continuous immunosuppressive therapy complicates this. Enhancing our understanding of the immune tolerance mechanisms related to graft rejection is crucial to generate safer transplantation strategies. This review will examine advancements in immune protection strategies for stem cell-derived islet therapy and discuss key clinical trials involving stem cell-derived β-cells and their protective strategies against the host immune system. Methods: A comprehensive literature search was performed on peer-reviewed publications on Google Scholar, Pubmed, and Scopus up to September 2024 to extract relevant studies on the various strategies of immune evasion of stem cell-derived β-cells in humans. The literature search was extended to assimilate all relevant clinical studies wherein stem cell-derived β-cells are transplanted to treat diabetes. Results: Our analysis highlighted the importance of human pluripotent stem cells (hPSCs) as a potentially unlimited source of insulin-producing β-cells. These cells can be transplanted as an effective source of insulin in diabetes patients if they can be protected against the host immune system. Various strategies of immune protection, such as encapsulation and genetic manipulation, are currently being studied and clinically tested. Conclusions: Investigating immune tolerance in hPSC-derived islets may help achieve a cure for diabetes without relying on exogenous insulin. Although reports of clinical trials show promise in reducing insulin dependency in patients, their safety and efficacy needs to be further studied to promote their use as a long-term solution to cure diabetes.

For patients suffering from organ failure due to injury or autoimmune disease, allogeneic organ transplantation with chronic immunosuppression is considered the god standard in terms of clinical treatment. However, the true "holy grail" of transplant immunology is operational tolerance, in which the recipient exhibits a sustained lack of alloreactivity toward unencountered antigen presented by the donor graft. This outcome is resultant from critical changes to the phenotype and genotype of the immune repertoire predicated by the activation of specific signaling pathways responsive to soluble and mechanosensitive cues. Biomaterials have emerged as a medium for interfacing with and reprogramming these endogenous pathways toward tolerance in precise, minimally invasive, and spatiotemporally defined manners. By viewing seminal and contemporary breakthroughs in transplant tolerance induction through the lens of biomaterials-mediated immunomodulation strategies-which include intrinsic material immunogenicity, the depot effect, graft coatings, induction and delivery of tolerogenic immune cells, biomimicry of tolerogenic immune cells, and in situ reprogramming-this review emphasizes the stunning diversity of approaches in the field and spotlights exciting future directions for research to come.

Recent progress in wound healing has highlighted the need for more effective treatment strategies capable of addressing the complex biological and physiological challenges of wound repair. Traditional wound dressings often fail to address the complex and evolving needs of chronic, acute, and burn wounds, particularly in terms of promoting healing, preventing infection, and supporting tissue regeneration. In response to these challenges, calcium alginate fibers (CAFs) have emerged as promising materials, characterized by their exceptional structural properties and diverse biological functions, offering significant commercial potential for the development of advanced wound dressings and therapeutic solutions. Here, a brief review of the CAFs for promoting wound healing is presented, with specific discussions of the fundamental characteristics of CAFs and its feasibility to be applied for adjusting physiological and pathological processes involved in wound healing. Then, a comprehensive and in-depth depiction of emerging representative fabrication techniques for generating CAFs is categorized and reviewed. Moreover, emerging applications benefits from the CAFs are reviewed, highlighting the multifunctional roles and benefits of CAFs in facilitating wound repair. Finally, the challenges and perspectives for further advancing CAFs toward a more powerful and versatile therapeutic strategy are discussed, particularly regarding new opportunities in biomedical research and clinical applications.

The multifaceted biological defense system modulating complex immune responses against pathogens and foreign materials plays a critical role in tissue homeostasis and disease progression. Recently developed biomaterials that can specifically regulate immune responses, nanoparticles, graphene, and functional hydrogels have contributed to the advancement of tissue engineering as well as disease treatment. The interaction between innate and adaptive immunity, collectively determining immune responses, can be regulated by mechanobiological recognition and adaptation of immune cells to the extracellular microenvironment. Therefore, applying immunomodulation to tissue regeneration and cancer therapy involves manipulating the properties of biomaterials by tailoring their composition in the context of the immune system. This review provides a comprehensive overview of how the physicochemical attributes of biomaterials determine immune responses, focusing on the physical properties that influence innate and adaptive immunity. This review also underscores the critical aspect of biomaterial-based immune engineering for the development of novel therapeutics and emphasizes the importance of understanding the biomaterials-mediated immunological mechanisms and their role in modulating the immune system.

Recent progress in stem cell therapy has demonstrated the therapeutic potential of intravenous stem cell infusions for treating the life-threatening lung disease of pulmonary fibrosis (PF). However, it is confronted with limitations, such as a lack of control over cellular function and rapid clearance by the host after implantation. In this study, we developed an innovative PF therapy through tracheal administration of microfluidic-templated stem cell-laden microcapsules, which effectively reversed the progression of inflammation and fibrotic injury. Our findings highlight that hydrogel microencapsulation can enhance the persistence of donor mesenchymal stem cells (MSCs) in the host while driving MSCs to substantially augment their therapeutic functions, including immunoregulation and matrix metalloproteinase (MMP)-mediated extracellular matrix (ECM) remodeling. We revealed that microencapsulation activates the MAPK signaling pathway in MSCs to increase MMP expression, thereby degrading overexpressed collagen accumulated in fibrotic lungs. Our research demonstrates the potential of hydrogel microcapsules to enhance the therapeutic efficacy of MSCs through cell-material interactions, presenting a promising yet straightforward strategy for designing advanced stem cell therapies for fibrotic diseases.

Immune reactions to medical implants often lead to encapsulation by fibrotic tissue and impaired device function. This process is thought to initiate by protein adsorption, which enables immune cells to attach and mount an inflammatory response. Previously, several antifibrotic materials have been either designed to reduce protein adsorption or discovered via high-throughput screens (HTS) to favorably regulate inflammation. The present work introduces antifouling immunomodulatory (AIM) copolymer coatings, which combine both strategies to effectively enhance implant protection. AIM copolymers synergistically integrate zwitterionic moieties to resist protein fouling, HTS-derived antifibrotics for immunomodulation, and silane monomers for grafting to diverse substrates including elastomers, ceramics, and metals. Interestingly, simply combining these monomers into conventional random or block copolymer architectures yielded no significant advantage over homopolymers. By contrast, an unusual polymer chain architecture - a zwitterionic block flanked by a mixed zwitterionic immunomodulatory segment - showed superior fibrosis resistance in both peritoneal and subcutaneous sites over one month in immunocompetent mice. This architecture also improved the performance of two different HTS-derived antifibrotic monomers, suggesting that tailoring AIM architectures may broadly complement immunomodulatory chemistries and provide a versatile approach to improving implant longevity.

Diabetes is a condition characterized by a loss of pancreatic β-cell function which results in the dysregulation of insulin homeostasis. Using a partial pancreatectomy model in axolotl, we aimed to observe the pancreatic response to injury.

Here we show a comprehensive histological assessment of pancreatic islets in axolotl. Following pancreatic injury, no apparent blastemal structure was observed. We found a significant, organ-wide increase in cellular proliferation post-resection in the pancreas compared to sham-operated controls. This proliferative response was most robust at the site of injury. We found that β-cells actively contributed to the increased rates of proliferation upon injury. β-cell proliferation manifested in increased β-cell mass in injured tissue at two weeks post injury. At four weeks post injury, we found organ-wide proliferation to be extinguished while proliferation at the injury site persisted, corresponding to pancreatic tissue recovery. Similarly, total β-cell mass was comparable to sham after four weeks.

Our findings suggest a non-blastema-mediated regeneration process takes place in the pancreas, by which pancreatic resection induces whole-organ β-cell proliferation without the formation of a blastemal structure. This process is analogous to other models of compensatory growth in axolotl, including liver regeneration.

Type 1 diabetes mellitus (T1DM) is a growing global health concern that affects approximately 8.5 million individuals worldwide. T1DM is characterized by an autoimmune destruction of pancreatic β cells, leading to a disruption in glucose homeostasis. Therapeutic intervention for T1DM requires a complex regimen of glycaemic monitoring and the administration of exogenous insulin to regulate blood glucose levels. Advances in continuous glucose monitoring and algorithm-driven insulin delivery devices have improved the quality of life of patients. Despite this, mimicking islet function and complex physiological feedback remains challenging. Pancreatic islet transplantation represents a potential functional cure for T1DM but is hindered by donor scarcity, variability in harvested cells, aggressive immunosuppressive regimens and suboptimal clinical outcomes. Current research is directed towards generating alternative cell sources, improving transplantation methods, and enhancing cell survival without chronic immunosuppression. This Review maps the progress in cell replacement therapies for T1DM and outlines the remaining challenges and future directions. We explore the state-of-the-art strategies for generating replenishable β cells, cell delivery technologies and local targeted immune modulation. Finally, we highlight relevant animal models and the regulatory aspects for advancing these technologies towards clinical deployment.

Transplanted cells can act as living drug factories capable of secreting therapeutic proteins in vivo, with applications in the treatment of Type 1 diabetes (T1D), blood borne disease, vision disorders, and degenerative neural disease, potentially representing functional cures for chronic conditions. However, attack from the host immune system represents a major challenge, requiring chronic immunosuppression to enable long-lived cell transplantation in vivo. Encapsulating cells in engineered biomaterials capable of excluding components of the host immune system while allowing for the transport of therapeutic proteins, oxygen, nutrients, metabolites, and waste products represents a potential solution. However, the foreign-body response can lead to isolation from native vasculature and hypoxia leading to cell death. In this prospective article, we highlight materials-based solutions to three important challenges in the field: (i) improving biocompatibility and reducing fibrosis; (ii) enhancing transport of secreted protein drugs and key nutrients and oxygen via engineered, semipermeable membranes; and (iii) improving oxygenation. These efforts draw on several disciplines in materials' research, including polymer science, surfaces, membranes, biomaterials' microfabrication, and flexible electronics. If successful, these efforts could lead to new therapies for chronic disease and are a rich space for both fundamental materials' discovery and applied translational science.

Cell-based drug factories could produce therapies on demand inside patients.

Stem cell-derived islets (SC-islets) offer the potential to be an unlimited source of cells for disease modeling and the treatment of diabetes. SC-islets can be genetically modified, treated with chemical compounds, or differentiated from patient derived stem cells to model diabetes. These models provide insights into disease pathogenesis and vulnerabilities that may be targeted to provide treatment. SC-islets themselves are also being investigated as a cell therapy for diabetes. However, the transplantation process is imperfect; side effects from immunosuppressant use have reduced SC-islet therapeutic potential. Alternative methods to this include encapsulation, use of immunomodulating molecules, and genetic modification of SC-islets. This review covers recent advances using SC-islets to understand different diabetes pathologies and as a cell therapy.

Transplantation of microencapsulated pancreatic cells is emerging as a promising therapy to replenish β-cell mass lost from auto-immune nature of type I diabetes mellitus (T1DM). This strategy intends to use micrometer-sized microgels to provide immunoprotection to transplanted cells to avoid chronic application of immunosuppression. Clinical application of encapsulation has remained elusive due to often limited production throughputs and body's immunological reactions to implanted materials. This article presents a high-throughput fabrication of monodisperse, non-immunogenic, non-degradable, immunoprotective, semi-permeable, enzymatically-crosslinkable polyethylene glycol-tyramine (PEG-TA) microgels for β-cell microencapsulation. Monodisperse β-cell laden microgels of ≈120 µm, with a shell thickness of 20 µm are produced using an outside-in crosslinking strategy. Microencapsulated β-cells rapidly self-assemble into islet-sized spheroids. Immunoprotection of the microencapsulated is demonstrated by inability of FITC-IgG antibodies to diffuse into cell-laden microgels and NK-cell inability to kill microencapsulated β-cells. Multiplexed ELISA analysis on live blood immune reactivity confirms limited immunogenicity. Microencapsulated MIN6β1 spheroids remain glucose responsive for 28 days in vitro, and able to restore normoglycemia 5 days post-implantation in diabetic mice without notable amounts of cell death. In short, PEG-TA microgels effectively protect implanted cells from the host's immune system while being viable and functional, validating this strategy for the treatment of T1DM.

Clinical studies on the treatment of type 1 diabetes with device-encapsulated pancreatic precursor cells derived from human embryonic stem cells found that insulin output was insufficient for clinical benefit. We are conducting a phase 1/2, open-label, multicenter trial aimed at optimizing cell engraftment (ClinicalTrials.gov identifier: NCT03163511 ). Here we report interim, 1-year outcomes in one study group that received 2-3-fold higher cell doses in devices with an optimized membrane perforation pattern. β cell function was measured by meal-stimulated plasma C-peptide levels at 3-month intervals, and the effect on glucose control was assessed by continuous glucose monitoring (CGM) and insulin dosing. Of 10 patients with undetectable baseline C-peptide, three achieved levels ≥0.1 nmol l-1 from month 6 onwards that correlated with improved CGM measures and reduced insulin dosing, indicating a glucose-controlling effect. The patient with the highest C-peptide (0.23 nmol l-1) increased CGM time-in-range from 55% to 85% at month 12; β cell mass in sentinel devices in this patient at month 6 was 4% of the initial cell mass, indicating directions for improving efficacy.

Multilayer conformal coatings have been shown to provide a nanoscale barrier between cells and their environment with adequate stability, while regulating the diffusion of nutrition and waste across the cell membrane. The coating method aims to minimize capsule thickness and implant volume while reducing the need for immunosuppressive drugs, making it a promising approach for islet cell encapsulation in clinical islet transplantation for the treatment of Type 1 diabetes. This study introduces an immunoprotective nanocoating obtained through electrostatic interaction between quaternized phosphocholine-chitosan (PC-QCH) and tetrahydropyran triazole phenyl-alginate (TZ-AL) onto mouse β-cell spheroids. First, successful synthesis of the proposed polyelectrolytes was confirmed with physico-chemical characterization. A coating with an average thickness of 540 nm was obtained with self-assembly of 4-bilayers of PC-QCH/TZ-AL onto MIN6 β-cell spheroids. Surface coating of spheroids did not affect cell viability, metabolic activity, or insulin secretion, when compared to non-coated spheroids. The exposure of the polyelectrolytes to THP-1 monocyte-derived macrophages lead to a reduced level of TNF-α secretion and exposure of coated spheroids to RAW264.7 macrophages showed a decreasing trend in the secretion of TNF-α and IL-6. In addition, coated spheroids were able to establish normoglycemia when implanted into diabetic NOD-SCID mice, demonstrating in vivo biocompatibility and cellular function. These results demonstrate the ability of the PC-QCH/TZ-AL conformal coating to mitigate pro-inflammatory responses from macrophages, and thus can be a promising candidate towards nanoencapsulation for cell-based therapy, particularly in type 1 diabetes, where the insulin secreting β-cells are subjected to inflammation and immune cell attack.

Alginate is a linear polysaccharide with a modifiable structure and abundant functional groups, offers immense potential for tailoring diverse alginate-based materials to meet the demands of biomedical applications. Given the advancements in modification techniques, it is significant to analyze and summarize the modification of alginate by physical, chemical and biological methods. These approaches provide plentiful information on the preparation, characterization and application of alginate-based materials. Physical modification generally involves blending and physical crosslinking, while chemical modification relies on chemical reactions, mainly including acylation, sulfation, phosphorylation, carbodiimide coupling, nucleophilic substitution, graft copolymerization, terminal modification, and degradation. Chemical modified alginate contains chemically crosslinked alginate, grafted alginate and oligo-alginate. Biological modification associated with various enzymes to realize the hydrolysis or grafting. These diverse modifications hold great promise in fully harnessing the potential of alginate for its burgeoning biomedical applications in the future. In summary, this review provides a comprehensive discussion and summary of different modification methods applied to improve the properties of alginate while expanding its biomedical potentials.

In recent years, the potential of stem cells (SCs) to differentiate into various types of cells, including β-cells, has led to a significant boost in development. The efficiency of this differentiation process and the functionality of the cells post-transplantation are crucial factors for the success of stem cell therapy in diabetes. Herein, this article reviews the current advances and challenges faced by stem cell differentiation into functional β-cells for diabetes treatment. In vitro, researchers have sought to enhance the differentiation efficiency of functional β-cells by mimicking the normal pancreatic development process, using gene manipulation, pharmacological and culture conditions stimulation, three-dimensional (3D) and organoid culture, or sorting for functional β-cells based on mature islet cell markers. Furthermore, in vivo studies have also looked at suitable transplantation sites, the enhancement of the transplantation microenvironment, immune modulation, and vascular function reconstruction to improve the survival rate of functional β-cells, thereby enhancing the treatment of diabetes. Despite these advancements, developing stem cells to produce functional β-cells for efficacious diabetes treatment is a continuous research endeavor requiring significant multidisciplinary collaboration, for the stem-cell-derived beta cells to evolve into an effective cellular therapy.

Cell therapies are emerging as a promising new therapeutic modality in medicine, generating effective treatments for previously incurable diseases. Clinical success of cell therapies has energized the field of cellular engineering, spurring further exploration of novel approaches to improve their therapeutic performance. Engineering of cell surfaces using natural and synthetic materials has emerged as a valuable tool in this endeavor. This review summarizes recent advances in the development of technologies for decorating cell surfaces with various materials including nanoparticles, microparticles, and polymeric coatings, focusing on the ways in which surface decorations enhance carrier cells and therapeutic effects. Key benefits of surface-modified cells include protecting the carrier cell, reducing particle clearance, enhancing cell trafficking, masking cell-surface antigens, modulating inflammatory phenotype of carrier cells, and delivering therapeutic agents to target tissues. While most of these technologies are still in the proof-of-concept stage, the promising therapeutic efficacy of these constructs from in vitro and in vivo preclinical studies has laid a strong foundation for eventual clinical translation. Cell surface engineering with materials can imbue a diverse range of advantages for cell therapy, creating opportunities for innovative functionalities, for improved therapeutic efficacy, and transforming the fundamental and translational landscape of cell therapies.

Diabetes mellitus, a chronic and non-transmissible disease, triggers a wide range of micro- and macrovascular complications. The differentiation of pancreatic β-like cells (PβLCs) from induced pluripotent stem cells (iPSCs) offers a promising avenue for regenerative medicine aimed at treating diabetes. Current differentiation protocols strive to emulate pancreatic embryonic development by utilizing cytokines and small molecules at specific doses to activate and inhibit distinct molecular signaling pathways, directing the differentiation of iPSCs into pancreatic β cells. Despite significant progress and improved protocols, the full spectrum of molecular signaling pathways governing pancreatic development and the physiological characteristics of the differentiated cells are not yet fully understood. Here, we report a specific combination of cofactors and small molecules that successfully differentiate iPSCs into PβLCs. Our protocol has shown to be effective, with the resulting cells exhibiting key functional properties of pancreatic β cells, including the expression of crucial molecular markers (pdx1, nkx6.1, ngn3) and the capability to secrete insulin in response to glucose. Furthermore, the addition of vitamin C and retinoic acid in the final stages of differentiation led to the overexpression of specific β cell genes.

Stem cell therapy (SCT) is a promising solution for addressing health challenges in Africa, particularly non-communicable diseases (NCDs). With their regenerative potential, stem cells have the inherent capacity to differentiate into numerous cell types for tissue repair. Despite infrastructural, ethical, and legal challenges, SCT holds immense promise for managing chronic illnesses and deep-seated tissue injuries. The rising prevalence of NCDs in Africa highlights the need for innovative strategies and treatment options. SCT offers hope in combating conditions like burns, osteoarthritis, diabetes, Alzheimer's disease, stroke, heart failure and cancer, potentially reducing the burden of NCDs on the continent. Despite SCT's opportunities in Africa, there are significant obstacles. However, published research on SCT in Africa is scarce, but recent initiatives such as the Basic School on Neural Stem Cells (NSC) express interest in developing NSC research in Africa. SCT research in African regions, notably on neurogenesis, demonstrates a concentration on studying neurological processes in indigenous settings. While progress has been made in South Africa and Nigeria, issues such as brain drain and impediments to innovation remain. Clinical trials have investigated the efficacy of stem cell treatments, emphasising both potential benefits and limitations in implementing these therapies efficiently. Financing research, developing regulatory frameworks, and resolving affordability concerns are critical steps toward realizing the potential of stem cell treatment in Africa.

The foreign body response (FBR) is an immune-mediated reaction that can occur with most biomaterials and biomedical devices. The FBR initiates a deterioration in the performance of implantable devices, representing a longstanding challenge that consistently hampers their optimal utilization. Over the last decade, significant strides are achieved based on either hydrogel design or surface modifications to mitigate the FBR. This review delves into recent material strategies aimed at mitigating the FBR. Further, the authors look forward to future novel anti-FBR materials from the perspective of clinical translation needs. Such prospective materials hold the potential to attenuate local immune responses, thereby significantly enhancing the overall performance of implantable devices.

There is an unrelenting interest in the development of a reliable bioartificial pancreas construct since the first description of this technology of encapsulated islets by Lim and Sun in 1980 because it promised to be a curative treatment for Type 1 Diabetes Mellitus (T1DM). Despite the promise of the concept of encapsulated islets, there are still some challenges that impede the full realization of the clinical potential of the technology. In this review, we will first present the justification for continued research and development of this technology. Next, we will review key barriers that impede progress in this field and discuss strategies that can be used to design a reliable construct capable of effective long-term performance after transplantation in diabetic patients. Finally, we will share our perspectives on areas of additional work for future research and development of the technology.

Cell encapsulation devices are expected to be promising tools that can control the release of therapeutic proteins secreted from transplanted cells. The protein permeability of the device membrane is important because it allows the isolation of transplanted cells while enabling the effectiveness of the device. In this study, we investigated free-standing polymeric ultra-thin films (nanosheets) as an intrinsically semi-permeable membrane made from polydimethylsiloxane (PDMS). The PDMS nanosheet with a thickness of 600 nm showed intrinsic protein permeability, and the device fabricated with the PDMS nanosheet showed that VEGF secreted from implanted adipose tissue-derived stem cells (ASCs) could be released for at least 5 days. The ASC encapsulation device promoted angiogenesis and the development of granulation tissue 1 week after transplantation to the subcutaneous area of a mouse. This cell encapsulation device consisting of PDMS nanosheets provides a new method for pre-vascularization of the subcutaneous area in cell transplantation therapy.

Diabetes is a prevalent chronic disease that traditionally requires severe reliance on medication for treatment. Oral medication and exogenous insulin can only temporarily maintain blood glucose levels and do not cure the disease. Most patients need life-long injections of exogenous insulin. In recent years, advances in islet transplantation have significantly advanced the treatment of diabetes, allowing patients to discontinue exogenous insulin and avoid complications.Long-term follow-up results from recent reports on islet transplantation suggest that they provide significant therapeutic benefit although patients still require immunotherapy, suggesting the importance of future transplantation strategies. Although organ shortage remains the primary obstacle for the development of islet transplantation, new sources of islet cells, such as stem cells and porcine islet cells, have been proposed, and are gradually being incorporated into clinical research. Further research on new transplantation sites, such as the subcutaneous space and mesenteric fat, may eventually replace the traditional portal vein intra-islet cell infusion. Additionally, the immunological rejection reaction in islet transplantation will be resolved through the combined application of immunosuppressant agents, islet encapsulation technology, and the most promising mesenchymal stem cells/regulatory T cell and islet cell combined transplantation cell therapy. This review summarizes the progress achieved in islet transplantation, and discusses the research progress and potential solutions to the challenges faced.

For cell therapies, the subcutaneous space is an attractive transplant site due to its large surface area and accessibility for implantation, monitoring, biopsy, and retrieval. However, its poor vascularization has catalyzed research to induce blood vessel formation within the site to enhance cell revascularization and survival. Most studies focus on the subcutaneous space of rodents, which does not recapitulate important anatomical features and vascularization responses of humans. Herein, we evaluate biomaterial-driven vascularization in the porcine subcutaneous space. Additionally, we report the first use of cost-effective fluorescent microspheres to quantify perfusion in the porcine subcutaneous space. We investigate the vascularization-inducing efficacy of vascular endothelial growth factor (VEGF)-delivering synthetic hydrogels based on 4-arm poly(ethylene) glycol macromers with terminal maleimides (PEG-4MAL). We compare three groups: a non-degradable hydrogel with a VEGF-releasing PEG-4MAL gel coating (Core+VEGF gel); an uncoated, non-degradable hydrogel (Core-only); and naïve tissue. After 2 weeks, Core+VEGF gel has significantly higher tissue perfusion, blood vessel area, blood vessel density, and number of vessels compared to both Core-only and naïve tissue. Furthermore, healthy vital signs during surgery and post-procedure metrics demonstrate the safety of hydrogel delivery. We demonstrate that VEGF-delivering synthetic hydrogels induce robust vascularization and perfusion in the porcine subcutaneous space.

The transplantation of immunoisolated stem cell derived beta cell clusters (SC-β) has the potential to restore physiological glycemic control in patients with type I diabetes. This strategy is attractive as it uses a renewable β-cell source without the need for systemic immune suppression. SC-β cells have been shown to reverse diabetes in immune compromised mice when transplanted as ≈300 µm diameter clusters into sites where they can become revascularized. However, immunoisolated SC-β clusters are not directly revascularized and rely on slower diffusion of nutrients through a membrane. It is hypothesized that smaller SC-β cell clusters (≈150 µm diameter), more similar to islets, will perform better within immunoisolation devices due to enhanced mass transport. To test this, SC-β cells are resized into small clusters, encapsulated in alginate spheres, and coated with a biocompatible A10 polycation coating that resists fibrosis. After transplantation into diabetic immune competent C57BL/6 mice, the "resized" SC-β cells plus the A10 biocompatible polycation coating induced long-term euglycemia in the mice (6 months). After retrieval, the resized A10 SC-β cells exhibited the least amount of fibrosis and enhanced markers of β-cell maturation. The utilization of small SC-β cell clusters within immunoprotection devices may improve clinical translation in the future.

Implantable medical devices that can facilitate therapy transport to localized sites are being developed for a number of diverse applications, including the treatment of diseases such as diabetes and cancer, and tissue regeneration after myocardial infraction. These implants can take the form of an encapsulation device which encases therapy in the form of drugs, proteins, cells, and bioactive agents, in semi-permeable membranes. Such implants have shown some success but the nature of these devices pose a barrier to the diffusion of vital factors, which is further exacerbated upon implantation due to the foreign body response (FBR). The FBR results in the formation of a dense hypo-permeable fibrous capsule around devices and is a leading cause of failure in many implantable technologies. One potential method for overcoming this diffusion barrier and enhancing therapy transport from the device is to incorporate local fluid flow. In this work, we used experimentally informed inputs to characterize the change in the fibrous capsule over time and quantified how this impacts therapy release from a device using computational methods. Insulin was used as a representative therapy as encapsulation devices for Type 1 diabetes are among the most-well characterised. We then explored how local fluid flow may be used to counteract these diffusion barriers, as well as how a more practical pulsatile flow regimen could be implemented to achieve similar results to continuous fluid flow. The generated model is a versatile tool toward informing future device design through its ability to capture the expected decrease in insulin release over time resulting from the FBR and investigate potential methods to overcome these effects.